Mild traumatic brain injury (mTBI) caused by blast effects of explosive devices is the ?signature injury? of Servicemembers deployed to combat operations in Iraq and Afghanistan. Resultant persistent postconcussive symptoms (PCS), such as impairment of memory and concentration, irritability, mood instability, sleep disturbances, and migraine headaches frequently have disabling personal, professional and domestic consequences. In addition to these immediate consequences, repetitive mTBI may initiate processes leading to neurodegeneration and dementia. This competitive renewal application proposes to continue longitudinally a currently funded VA RR&D Merit Review: B77421, Mild TBI and Biomarkers of Neurodegeneration. In the current funding period, we have made substantial progress in 1) identifying objective structural and functional neuroimaging biomarkers that characterize the clinical phenotype of blast-induced mTBI, 2) identifying objective impairment and longitudinal decline in cognitive function in mTBI Veterans using our refined neuropsychological assessment battery, and 3) identifying in cerebrospinal fluid (CSF) and plasma a group mTBI-specific inter-related neuroinflammatory chemoattractant, vascular disturbance, and neurodegeneration biomarkers. We have integrated neuroimaging, cognitive, and biomarker findings into a consistent model of regional cerebellar- thalamic-frontoparietal cortical and brainstem dysfunction in repetitive blast mTBI. Goals of this continuation proposal are to determine whether cognitive performance is associated with neuroimaging and/or CSF and plasma biomarkers of mTBI and/or genetic risk factors for neurodegenerative dementia, and to determine whether neuroimaging and CSF and plasma biomarker abnormalities are transient, static, or progressive. We also propose 1) a new plasma biomarker goal: central nervous system (CNS)-derived plasma exosomal cargo proteins, 2) new clinical assessments of sleep: in-theater sleep history and sleep/activity monitoring via Actigraphy, and 3) an additional advanced neuroimaging analyses: diffusion tensor imaging Automating-Fiber- Tract Quantification. Specific Aim 1: To continue characterizing longitudinally the clinical (neurocognitive, neurologic, behavioral) and structural/functional neuroimaging characteristics of disrupted cerebellar-thalamic-frontoparietal cortical and brainstem function in OIF/OEF/OND Veterans with repetitive blast trauma mTBI. Specific Aim 2: To determine if OEF/OIF/OND Veterans with repetitive mTBI exhibit CSF and plasma neurovascular, neuroinflammatory, and neurodegeneration biomarker changes associated with the onset and progression of neurodegenerative dementing disorders. Specific Aim 3: To determine the effects of genetic risk factors for neurodegeneration (apolipoprotein E [APOE] polymorphisms and microtubule associated protein tau [MAPT] subhaplotypes) on clinical characteristics and neuroimaging and biofluid biomarkers in OEF/OIF/OND Veterans with repetitive mTBI. This proposal is in response to RFA RX-18-014: Studies on the Chronic Effects of Neurotrauma and focuses on the long-term consequences of repetitive mTBI. By identifying objective neuroimaging and CSF and plasma biomarkers of blast mTBI and neurodegenerative dementias, the proposed research has potential for: 1) improving the accuracy of blast mTBI diagnoses; 2) identifying clinical characteristics and biomarkers of blast mTBI that suggest potential treatments and provide the ability to track response to potential treatments; and 3) identifying health care needs unique to blast mTBI Veterans. Successful completion of the proposed research has a high likelihood of yielding both short-term and long-term clinical impacts. The project will yield tools for objective biomarker diagnosis of mTBI and form the evidence base for rational design of clinical trials to treat current symptoms of mTBI and to prevent progression to neurodegenerative dementing disorders.